A Diagnostic Platform for Extracellular Vesicle-Derived Biomarkers - Towards Early Detection of Alzheimer's Disease

细胞外囊泡衍生生物标志物的诊断平台 - 迈向阿尔茨海默病的早期检测

• 批准号: 10629620
• 负责人: Kristen Dellinger
• 金额: $ 14.07万
• 依托单位: NORTH CAROLINA AGRI & TECH ST UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629620
• 关键词: Address; Affect; Affinity; Alzheimer disease detection; Alzheimer disease screening; Alzheimer' s Disease; Alzheimer' s disease care; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Amyloid beta-42; Amyloid beta-Protein; Area; Binding; Biological; Biological Assay; Biological Markers; Biomedical Research; Biosensing Techniques; Biosensor; Blood; Blood specimen; Caring; Cerebrospinal Fluid; Characteristics; Clinical; Clinical assessments; Cognitive; Cognitive Therapy; Complex; Coupled; Dementia; Detection; Development; Devices; Diagnosis; Disease; Early Diagnosis; Early Intervention; Effectiveness of Interventions; Endowment; Engineering; Environment; Enzyme-Linked Immunosorbent Assay; Executive Dysfunction; Exhibits; Experimental Designs; Foundations; Goals; Gold; Human; Impaired cognition; Individual; Institutionalization; Language; Long-Term Care; Molecular; Monitor; Neurofibrillary Tangles; Neurons; North Carolina; Optics; Participant; Patients; Pharmacologic Substance; Positioning Attribute; Protein Isoforms; Proteins; Raman Spectrum Analysis; Rapid screening; Recording of previous events; Research; Research Support; Sampling; Screening procedure; Senile Plaques; Sensitivity and Specificity; Serum; Societies; Source; Specificity; Spectrum Analysis; Spinal Puncture; Surface; Symptoms; Technology; Time; Treatment outcome; Underrepresented Populations; United States National Institutes of Health; Universities; Update; Visuospatial; Western Blotting; Work; biochip; care costs; clinical diagnostics; clinical practice; cost effective; design; detection limit; diagnostic criteria; diagnostic platform; diagnostic screening; early detection biomarkers; economic cost; effective intervention; extracellular vesicles; graduate student; improved; induced pluripotent stem cell; multidisciplinary; novel; patient prognosis; point of care; pre-clinical; predictive marker; prognostic tool; rational design; routine practice; routine screening; screening; societal costs; tau Proteins; tau-1; tool; undergraduate student

A Diagnostic Platform for Extracellular Vesicle-Derived Biomarkers: Towards Early Detection of Alzheimer’s Disease PROJECT SUMMARY. Alzheimer’s disease (AD) poses a growing burden on our society, with cases expected to reach 12.7 million by 2050. While research supports biomarkers for early detection, most Alzheimer’s patients are diagnosed after exhibiting clinical symptoms. At this stage, the advanced progression of senile plaques and neurofibrillary tangles pose significant challenges to effective interventions. Moreover, established biomarkers, such as amyloid beta-42/amyloid beta-40 and phosphorylated tau, are currently limited to analysis in cerebrospinal fluid, making their potential for routine screening nearly impossible. Thus, there is a critical need for novel, non-invasive approaches to rapidly screen for preclinical Alzheimer’s to facilitate the application of early interventions, such as physical, pharmaceutical, and cognitive therapies. Recent work has demonstrated the potential of circulating extracellular vesicles as a promising source of biomarkers to monitor and diagnose various diseases, including AD. However, accessible technologies to accurately detect AD-associated extracellular vesicles and their constituents are not currently in clinical practice. Moreover, concentrations in blood are present in the low pico- to femtomolar range, limiting conventional detection by ELISA and Western blot. This proposal aims to address these critical needs and focuses on developing a new platform to detect tau in neuron-derived extracellular vesicles (NDEVs). We hypothesize that ultrasensitive detection (< 5 pg/mL) of NDEV-tau can be achieved by optimizing our surface-enhanced Raman spectroscopy (SERS) nanotag technology using a rational design-of-experiment approach. If our hypothesis is correct, we expect this work to serve as the foundation for developing a point-of-care device that can be used for routine screening of pre-symptomatic AD. With this goal in mind, we will focus on the following specific aims: (1) Synthesize ‘SERS nanotags’ with a high affinity for NDEV-tau and identify the characteristics for effective binding; (2) Assess NDEV-tau sensitivity and specificity using the SERS platform in spiked human serum. Ultimately, we expect to establish the limit of detection and sample volumes needed for accurate tau detection. By engineering SERS-active substrates for ultrasensitive detection of NDEV-tau, we can then build upon this platform to enhance the multiplexing of several AD-associated biomarkers in complex biological samples. Our long-term goal is to develop SERS-based bioanalysis to drastically improve current standards in molecular detection for AD in both clinical and research settings.

细胞外囊泡衍生的生物标志物的诊断平台： 渴望早期发现阿尔茨海默氏病 项目摘要。 阿尔茨海默氏病（AD）对我们的社会施加了越来越多的烧伤，预计案件将达到1,270万 到2050年。尽管研究支持早期检测的生物标志物，但大多数阿尔茨海默氏症患者被诊断出 表现出临床症状后。在此阶段，老年斑块的高级进展和 神经纤维缠结对有效干预构成了重大挑战。而且，建立 生物标志物，例如淀粉样蛋白β-42/淀粉样蛋白β-40和磷酸化的tau，目前仅限于 在脑脊液中的分析，几乎不可能进行常规筛查的潜力。那是 对新颖的非侵入性方法的批判性需要快速筛选临床前阿尔茨海默氏症 早期干预措施（例如物理，药物和认知疗法）的应用。最近的 工作已经证明了循环细胞外蔬菜作为生物标志物的希望来源的潜力 监测和诊断各种疾病，包括AD。但是，可访问的技术准确 检测到与AD相关的细胞外蔬菜及其结构目前尚未在临床实践中。 此外，血液中的浓度在低pico- to-tol摩尔范围内呈现，限制了常规 Elisa和Western印迹的检测。该建议旨在满足这些关键需求，并关注 开发一个新的平台，以检测神经衍生的细胞外蔬菜（NDEV）中的tau。我们假设 可以通过优化我们的表面增强物来实现NDEV-TAU的超敏感检测（<5 pg/ml） 拉曼光谱（SERS）纳米塔技术采用合理的实验设计方法。如果我们 假设是正确的，我们希望这项工作将成为开发护理设备的基础 可用于常规筛选症状AD。考虑到这个目标，我们将专注于 以下特定目的：（1）合成对NDEV-TAU具有高亲和力的“ sers nanotags”并确定 有效结合的特征； （2）使用SERS平台评估NDEV-TAU的敏感性和特异性 在尖刺的人血清中。最终，我们期望建立所需的检测和样品量的极限 为了准确检测。通过工程活性底物，用于对NDEV-TAU的超敏感检测， 然后，我们可以在这个平台上构建以增强在 复杂的生物样品。我们的长期目标是开发基于SERS的生物分析以急剧 在临床和研究环境中，提高了AD分子检测的当前标准标准。